Biktarvy® (BIC/FTC/TAF)

Use in Baseline INSTI Resistance

This document is in response to your request for information regarding Biktarvy® (bictegravir/emtricitabine/tenofovir alafenamide [BIC/FTC/TAF]) and its use in patients with baseline integrase strand transfer inhibitor resistance (INSTI-R).

Some data may be outside of the US FDA-approved prescribing information. In providing this data, Gilead Sciences, Inc. is not making any representation as to its clinical relevance or to the use of any Gilead product(s). For information about the approved conditions of use of any Gilead drug product, please consult the FDA-approved prescribing information.

The full indication, important safety information, and boxed warnings are available at:
www.gilead.com/-/media/files/pdfs/medicines/hiv/biktarvy/biktarvy_pi.

Summary

Product Labeling1

BIC/FTC/TAF is not indicated to be used in individuals with known or suspected substitutions associated with resistance to BIC or tenofovir.

Clinical Data on BIC/FTC/TAF Use in Participants With Baseline INSTI Resistance

In a pooled analysis of seven phase 3 studies that included ARV-naïve and virologically suppressed participants who initiated or switched to BIC/FTC/TAF for 48 weeks, 20/1906 participants had preexisting primary INSTI-R substitutions, 19 of whom remained virologically suppressed through Week 48 with no viral blips. The remaining participant with preexisting INSTI-R substitutions achieved virological suppression at Week 4 and maintained through Week 216.2,3

Clinical Data on BIC/FTC/TAF Use in Participants With Baseline INSTI-R

Pooled Analysis of Virologic Outcomes After 48 Weeks

Study design and baseline demographics2

A pooled analysis of seven phase 3 studies was conducted to determine the virologic outcomes after 48 weeks of BIC/FTC/TAF treatment in ARV-naïve participants who initiated BIC/FTC/TAF and virologically suppressed participants who switched to BIC/FTC/TAF with preexisting INSTI-R (Table 1). Known INSTI-R was an exclusion criterion prior to study enrollment; however, participants with preexisting INSTI-R identified post-enrollment were permitted to continue in the studies.

Table 1. Pooled Analysis: Overview of BIC/FTC/TAF Studies2

aPrior INSTI use was allowed if there was no prior virological failure on the INSTI-based regimen.

Efficacy results at Week 48

Preexisting primary INSTI-R substitutions were observed in 1% of participants (20/1906) post-enrollment. Of the 20 participants with preexisting primary INSTI-R, 75% were male, 55% were Black, and 85% had HIV-1 subtype B. The most frequent primary INSTI-R mutations identified were Y143C/H and Q148H/K/R (Table 2).2

Table 2. Pooled Analysis: Primary INSTI-R Mutations in BIC/FTC/TAF Studies2

Of the 20 participants with primary preexisting INSTI-R substitutions, 19 participants were from studies that included virologically suppressed participants, and 100% of these participants maintained HIV-1 RNA <50 c/mL at all study visits through Week 48 with no viral blips.2

One ARV-naïve participant was retrospectively identified who had transmitted INSTI-R, NRTI-R, and NNRTI-R. The INSTI-R mutations G140S + Q148H were detected, with phenotypic sensitivity to BIC (<2.5-fold change) and partial sensitivity to DTG. After treatment with BIC/FTC/TAF, HIV-1 RNA <50 c/mL was achieved at Week 4 and maintained through Week 216.2,3

Studies 1489 and 1490 OLE analysis in participants with preexisting INSTI-R

Efficacy results from OLE phase

BIC/FTC/TAF demonstrated non-inferior efficacy (HIV-1 RNA <50 c/mL) to DTG/ABC/3TC (Study 1489) and DTG + FTC/TAF (Study 1490) by FDA Snapshot analysis at the Week 48 primary endpoint and the secondary endpoints at Weeks 96 and 144.4 Preexisting primary INSTI-R using a mutation frequency cut-off of ≥15% was discovered in 7 participants taking BIC/FTC/TAF; 100% of these participants were virologically suppressed at Week 144.5

Safety results at Week 1444

A safety analysis was not conducted in the subgroup of participants with INSTI-R at baseline. The most common all-grade adverse reactions reported in ≥10% of all participants in the BIC/FTC/TAF arms in either study through Week 144 were nausea, diarrhea, URTI, headache, nasopharyngitis, back pain, fatigue, cough, and syphilis. AEs led to study drug discontinuation in no participants in the BIC/FTC/TAF arm in Study 1489 and in 6 participants (2%) in the BIC/FTC/TAF arm in Study 1490.

Studies 1878 and 1844 OLE analysis in participants with preexisting INSTI-R

Efficacy results from OLE phase

At Week 48, 561/570 (98%) of the pooled BIC/FTC/TAF group, 280/285 (98%) of the PI + 2 NRTIs group, and 280/281 (>99%) of the DTG/ABC/3TC group achieved virological suppression.6 In Study 1878, 14/14 participants with baseline INSTI-R taking BIC/FTC/TAF for a median duration of 103 weeks had HIV-1 RNA <50 c/mL at their last visit.7 In Study 1844, 16/16 participants with baseline INSTI-R taking BIC/FTC/TAF for a median duration of 96 weeks had HIV-1 RNA <50 c/mL at their last visit.8

Safety results

A safety analysis was not conducted in the subgroup of participants with INSTI-R at baseline. In Study 1878, the most common all-grade adverse reactions reported in ≥10% of all participants taking ≥1 dose of BIC/FTC/TAF through a median exposure of 101 weeks were headache, nasopharyngitis, URTI, and diarrhea.9 AEs led to study drug discontinuation in 6 participants (1%) in the pooled BIC/FTC/TAF group. In Study 1844, the most common all-grade adverse reactions reported in ≥10% of all participants taking ≥1 dose of BIC/FTC/TAF through a median exposure of 96 weeks were URTI, nasopharyngitis, and diarrhea. AEs led to study drug discontinuation in 7 participants (1%) in the pooled BIC/FTC/TAF group.8

Study 4030 safety through Week 4810

A safety analysis was not conducted in the subgroup of participants with INSTI-R at baseline. In the overall safety analysis, the most commonly reported AEs reported by ≥10% in either group were nasopharyngitis, diarrhea, and URTI. Drug-related AEs occurring at ≥2% in either group were diarrhea and headache. Six participants (2%) in each arm discontinued the study because of AEs.

Study 4580 (BRAAVE) OLE analysis in participants with preexisting INSTI-R

Efficacy results through Week 72

Switching to BIC/FTC/TAF was noninferior to continuing the baseline regimen of 2 NRTIs plus a third agent by FDA Snapshot analysis at the Week 24 primary endpoint.11 High rates of virologic suppression were maintained through Week 72 in BIC/FTC/TAF and delayed‑switch arms (99% and 100%, respectively, in a missing=excluded analysis).12

Although primary INSTI-R was an exclusion criterion, 2% of participants were found to have preexisting primary INSTI-R (Table 3).13

Table 3. BRAAVE 2020: Proportion of Participants With Preexisting INSTI‑R Substitutions13

aResistance category corrected per author communication.

bY143C and Q148K were detected by historical genotype in 1 participant each; both participants were excluded from efficacy analyses but maintained virologic suppression at all study visits through Week 24.

Through Week 72, 99% (486/489) of the pooled BIC/FTC/TAF group and 100% (11/11) of participants with preexisting INSTI-R had virologic suppression at their last study visit.13

Safety results

A safety analysis was not conducted in the subgroup of participants with INSTI-R at baseline. In the overall safety analysis, switching to BIC/FTC/TAF was well tolerated, and reported AEs were comparable between the two treatment arms at Week 24.11 All-grade AEs that occurred in ≥5% of participants receiving BIC/FTC/TAF at any time (n=493) included URTI, syphilis, headache, pain in extremity, arthralgia, hypertension, and nasopharyngitis. AEs led to 6 study drug discontinuations between baseline and Week 24, 3 discontinuations between Weeks 24 and 48, and 3 discontinuations after Week 48.12

References

1. Enclosed, Gilead Sciences Inc. BIKTARVY® (bictegravir, emtricitabine, and tenofovir alafenamide) tablets, for oral use. US Prescribing Information. Foster City, CA.

2. D'Antoni ML, Andreatta K, Acosta R, et al. Brief Report: Bictegravir/Emtricitabine/Tenofovir Alafenamide Efficacy in Participants With Preexisting Primary Integrase Inhibitor Resistance Through 48 Weeks of Phase 3 Clinical Trials. J Acquir Immune Defic Syndr. 2022;89(4):433-440.

3. White K, Kulkarni R, Willkom M, et al. Pooled Week 48 Efficacy and Baseline Resistance: B/F/TAF in Treatment-Naive Patients [Poster 532]. Paper presented at: Conference on Retroviruses and Opportunistic Infections (CROI); 04-07 March, 2018; Boston, MA.

4. Orkin C, DeJesus E, Sax PE, et al. Three-Year Outcomes of the Fixed-Dose Combination Bictegravir, Emtricitabine, and Tenofovir Alafenamide vs Dolutegravir-Containing Regimens for Initial Treatment of HIV-1 Infection: Week 144 Results from Two Randomised, Double-Blind, Multicentre, Phase 3, Non-Inferiority Trials. The Lancet HIV. 2020;7:e389–400.

5. Acosta RK, Chen GQ, Chang S, et al. Three-year study of pre-existing drug resistance substitutions and efficacy of bictegravir/emtricitabine/tenofovir alafenamide in HIV-1 treatment-naive participants. J Antimicrob Chemother. 2021.

6. Andreatta K, Willkom M, Martin R, et al. Switching to Bictegravir/Emtricitabine/Tenofovir Alafenamide Maintained HIV-1 RNA Suppression in Participants with Archived Antiretroviral Resistance Including M184V/I. J Antimicrob Chemother. 2019. https://www.ncbi.nlm.nih.gov/pubmed/31430369

7. Andreatta K, Chang S, Delaney M, et al. Long-term Efficacy of Bictegravir/Emtricitabine/Tenofovir Alafenamide After Switch From Boosted Protease Inhibitor-Based Regimens Including in Those With Preexisting Resistance and Viral Blips [Poster PE1/19]. Paper presented at: 18th European AIDS Conference; October 27-30, 2021; London, United Kingdom.

8. Brar I, Ruane P, Ward D, et al. Long-term Follow-up After a Switch to Bictegravir, Emtricitabine, and Tenofovir Alafenamide From Dolutegravir, Abacavir, and Lamivudine [Poster 1028]. Paper presented at: IDWeek Virtual; 21-25 October, 2020.

9. Rockstroh JK, Molina JM, Post F, et al. Long-Term Follow-Up After a Switch to Bictegravir, Emtricitabine, Tenofovir Alafenamide (B/F/TAF) from a Boosted Protease Inhibitor-Based Regimen [Poster P036]. Paper presented at: HIV GLASGOW Drug Therapy Virtual; 05-08 October, 2020; Glasgow, UK.

10. Sax PE, Rockstroh JK, Luetkemeyer AF, et al. Switching to bictegravir, emtricitabine, and tenofovir alafenamide in virologically suppressed adults with Human Immunodeficiency Virus. Clin Infect Dis. 2020:1-9.

11. Hagins D, Kumar P, Saag M, et al. Switching to Bictegravir/Emtricitabine/Tenofovir Alafenamide in Black Americans With HIV-1: A Randomized Phase 3b, Multicenter, Open-Label Study. J Acquir Immune Defic Syndr. 2021;88(1):86-95.

12. Kumar P, Stephens JL, Wurapa AK, et al. Week 72 Outcomes and COVID-19 Impact From the BRAAVE 2020 Study: a Randomized Switch to B/F/TAF in Black American Adults With HIV [Poster 802]. Paper presented at: 11th International AIDS Society (IAS) Conference on HIV Science Virtual; 18-21 July, 2021.

13. Andreatta K, D'Antoni ML, Chang S, et al. High Efficacy of Bictegravir/Emtricitabine/Tenofovir Alafenamide in African-American Adults With HIV Including Those with Preexisting Resistance, Viral Blips, and Suboptimal Adherence [Poster 629]. Paper presented at: IDWeek Virtual; 29 Sept-03 Oct, 2021.

Abbreviations

3TC=lamivudine
ABC=abacavir
AE=adverse event
ARV=antiretroviral
BIC=bictegravir
c/mL=copies/mL
DTG=dolutegravir
FTC=emtricitabine
INSTI=integrase strand transfer inhibitor
INSTI-R=integrase strand transfer inhibitor resistance
NNRTI-R=non-nucleos(t)ide reverse transcriptase inhibitor resistance
NRTI=nucleos(t)ide reverse transcriptase inhibitor
NRTI-R=nucleos(t)ide reverse transcriptase inhibitor resistance
OLE=open-label extension
PI=protease inhibitor
TAF=tenofovir alafenamide
URTI=upper respiratory infection
 

Product Label

For the full indication, important safety information, and boxed warning(s), please refer to the Biktarvy US Prescribing Information available at:
www.gilead.com/-/media/files/pdfs/medicines/hiv/biktarvy/biktarvy_pi.

Follow-Up

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